L-carnitine 3-hydroxy-4-(trimethylamino-)butyrate is a naturally occurring quaternary amine that is required in energy metabolism in mammals. The L-carnitine molecule has been shown to promote oxidation of branched-chain amino acids, the utilization of acetyl-coenzyme A, and the removal of extra or “toxic” acyl groups from the mitochondria and cell as carnitine esters. Arguably its most important function, however, is the promotion of beta-oxidation of long chain fatty acids by facilitating their transfer across the mitochondrial membrane.
Because of its central role in transporting fatty acids to the site of oxidation, adequate levels of L-carnitine are required for normal fatty acid and energy metabolism in those tissues, such as the heart, which preferentially metabolize fatty acids. In the human, L-carnitine is synthesized endogenously from the amino acids, lysine and methionine. Meat products, particularly red meats (beef, lamb and pork) and dairy products are important dietary sources of L-carnitine. None-the-less, carnitine deficiency can occur in humans ad presents a characteristic syndrome. Affected individuals may display mild to severe muscle weakness, hypoglycemia, liver dysfunction and cardiomyopathy. It detected early, the syndrome is often completely reversible with daily administration of adequate amounts of L-carnitine.
Gamma-butyrobetaine (“GBB”) is the immediate precursor to L-carnitine in the biosynthetic pathway of the latter compound. It is disclosed in U.S. Pat. No. 4,382,092, incorporated herein by reference, that GBB given orally will be readily converted to L-carnitine in carnitine deficient patients and is thus a suitable substitute for L-carnitine in treating such deficiencies. GBB has the advantage of being much less expensive to chemically synthesize than is L-carnitine. Hereafter, the term “carnitine” will be understood to refer to either L-carnitine or GBB, as well as their biologically active salts and esters, but not D-carnitine, the latter compound being hereby specifically excluded.
Some forms of organic aciduria have been treated with L-carnitine administration. In some such cases the affected individual must be given as much as 400 mg/k/day of L-carnitine.
Carnitine is also considered by some authorities to be a useful and important nutritional supplement, particularly for older persons who frequently show elevated esterified carnitine levels in the serum. Some evidence exists that carnitine supplementation enhances the immune system, muscle efficiency, and overall well being of the person using carnitine supplementation.
More recently, it has been found that carnitine is useful in patients suffering from or predisposed to osteoporosis. In such individuals it is believed that daily administration of carnitine will reduce the loss of bone mass. Co-pending U.S. application Ser. No. 07/907,847, incorporated herein by reference, discloses that daily administration of carnitine in amounts from 50 to 200 mg/kilogram will result in a significantly reduced loss of bone mass.
Oral formulations of L-carnitine are available in tablet or capsule form. The inventors are not aware of any commercially available oral dosage formulation of GBB. None of the heretofore known oral formulations of L-carnitine provide a sustained release of L-carnitine. Common dosage forms of the presently available oral formulations are usually 250 to 500 mg per tablet or capsule. Principal suppliers of pharmaceutical grade L-carnitine are Sigma Tau SpA, Rome, Italy; Aginomoto, Terrance, Calif.; and Lanza Chemical Company, Berne, Switzerland.
Where L-carnitine is being administered to treat carnitine deficiency dosages as high as 400 mg/K/day may have to be given. The customary dosage amount for mild to moderate carnitine deficiency is 50 to 100 mg/k/day.
Because the half-life of L-carnitine in the human is approximately 30 minutes, the usual dosage regimen is to administer an excess amount of L-carnitine four times each day. If the dosage formulation is 250 mg/tablet, one would expect a 70 kilogram mildly deficient individual to take 7 tablets, four times each day (or 28 tablets/day) in order to restore L-carnitine to normal plasma levels.
A number of disadvantages exist with the presently available dosage forms of L-carnitine. First, the renal threshold for L-carnitine is about 80 to 120 microM/L. This threshold is invariably exceeded when large amounts of L-carnitine are given and thus much of the otherwise useful L-carnitine is “dumped” in the urine. Second, L-carnitine is subject to breakdown by the bacteria of the gut and when large boluses of the drug are given, a fair amount is lost through bacterial breakdown. Third, L-carnitine can cause gastrointestinal irritation resulting in gastrointestinal distress and diarrhea. Such problems are exacerbated when frequency of administration and dosage levels are both high.
The present invention avoids most, if not all, of the above stated disadvantages. Additionally, it allows for a much more convenient dosage regimen (e.g., once or twice per day) with greater efficacy than its nonsustained release counterpart.